CA2042112C - N'-alkylspiro-isoquinoleinepyrrolidinetetrones et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase - Google Patents

N'-alkylspiro-isoquinoleinepyrrolidinetetrones et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase Download PDF

Info

Publication number: CA2042112C
Authority: CA; Canada
Prior art keywords: carbon atoms; aryl; lower alkyl; formula; compound
Prior art date: 1990-05-21
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Fee Related

Application number

CA002042112A

Other languages

English (en)

Other versions

CA2042112A1 (fr

Inventor

Michael S. Malamas

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Wyeth LLC

Original Assignee

American Home Products Corp

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1990-05-21

Filing date

1991-05-08

Publication date

2001-07-24

1991-05-08 Application filed by American Home Products Corp filed Critical American Home Products Corp

1991-05-08 Priority to CA002324636A priority Critical patent/CA2324636A1/fr

1991-11-22 Publication of CA2042112A1 publication Critical patent/CA2042112A1/fr

2001-07-24 Application granted granted Critical

2001-07-24 Publication of CA2042112C publication Critical patent/CA2042112C/fr

2011-05-08 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title claims abstract description 33
239000003288 aldose reductase inhibitor Substances 0.000 title description 2
229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 78
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 69
125000000217 alkyl group Chemical group 0.000 claims abstract description 65
125000003118 aryl group Chemical group 0.000 claims abstract description 57
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
239000001257 hydrogen Substances 0.000 claims abstract description 18
206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
229910052736 halogen Inorganic materials 0.000 claims abstract description 13
IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims abstract description 12
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 12
125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
150000002367 halogens Chemical class 0.000 claims abstract description 9
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
125000002252 acyl group Chemical group 0.000 claims abstract description 7
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 20
239000002904 solvent Substances 0.000 claims description 19
238000000034 method Methods 0.000 claims description 15
150000002431 hydrogen Chemical class 0.000 claims description 12
-1 4-bromo-2-fluorophenyl Chemical group 0.000 claims description 11
230000008569 process Effects 0.000 claims description 7
229910006124 SOCl2 Inorganic materials 0.000 claims description 5
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
241000124008 Mammalia Species 0.000 claims description 4
150000007529 inorganic bases Chemical class 0.000 claims description 4
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BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 claims description 4
XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 claims description 3
208000017442 Retinal disease Diseases 0.000 claims description 3
206010038923 Retinopathy Diseases 0.000 claims description 3
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VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 claims description 2
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UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
239000008194 pharmaceutical composition Substances 0.000 claims description 2
125000003107 substituted aryl group Chemical group 0.000 claims description 2
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125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 4
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150000003839 salts Chemical class 0.000 abstract description 2
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
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ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
239000000203 mixture Substances 0.000 description 25
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
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238000006243 chemical reaction Methods 0.000 description 12
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
238000005160 1H NMR spectroscopy Methods 0.000 description 11
229910052943 magnesium sulfate Inorganic materials 0.000 description 11
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
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NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 9
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
239000008103 glucose Substances 0.000 description 9
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
239000000243 solution Substances 0.000 description 8
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108010053754 Aldehyde reductase Proteins 0.000 description 7
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239000002253 acid Substances 0.000 description 7
238000003818 flash chromatography Methods 0.000 description 7
229910000104 sodium hydride Inorganic materials 0.000 description 7
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239000003039 volatile agent Substances 0.000 description 7
102000004877 Insulin Human genes 0.000 description 6
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DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
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BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
210000000695 crystalline len Anatomy 0.000 description 5
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BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 5
FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 5
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GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 4
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
238000005481 NMR spectroscopy Methods 0.000 description 4
YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 4
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125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
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238000002360 preparation method Methods 0.000 description 4
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JQPCNISBBBPSOS-UHFFFAOYSA-N 2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)benzoic acid Chemical compound COC(=O)C(C(=O)OC)C1=CC=CC=C1C(O)=O JQPCNISBBBPSOS-UHFFFAOYSA-N 0.000 description 3
XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 3
FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 3
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GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
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KRGISNPUOYXUBW-UHFFFAOYSA-N 2-[2-[(4-bromo-2-fluorophenyl)methyl]-6-fluoro-4-methoxycarbonyl-1,3-dioxoisoquinolin-4-yl]acetic acid Chemical compound O=C1C2=CC=C(F)C=C2C(C(=O)OC)(CC(O)=O)C(=O)N1CC1=CC=C(Br)C=C1F KRGISNPUOYXUBW-UHFFFAOYSA-N 0.000 description 2
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CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
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AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
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WAAUNVUMROVZIW-UHFFFAOYSA-N methyl 2-(cyanomethyl)-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)C(=O)N(CC#N)C(=O)C2=C1 WAAUNVUMROVZIW-UHFFFAOYSA-N 0.000 description 2
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239000011737 fluorine Chemical group 0.000 description 1
230000004907 flux Effects 0.000 description 1
230000004190 glucose uptake Effects 0.000 description 1
238000000338 in vitro Methods 0.000 description 1
239000003701 inert diluent Substances 0.000 description 1
239000003112 inhibitor Substances 0.000 description 1
230000000977 initiatory effect Effects 0.000 description 1
206010023365 keratopathy Diseases 0.000 description 1
210000003734 kidney Anatomy 0.000 description 1
239000008101 lactose Substances 0.000 description 1
239000010410 layer Substances 0.000 description 1
230000007774 longterm Effects 0.000 description 1
ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
239000001095 magnesium carbonate Substances 0.000 description 1
229910000021 magnesium carbonate Inorganic materials 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
239000000463 material Substances 0.000 description 1
208000030159 metabolic disease Diseases 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
MWKKTHKUEVFYQR-UHFFFAOYSA-N methyl 2-(cyanomethyl)-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxoisoquinoline-4-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)(CC(=O)OC(C)(C)C)C(=O)N(CC#N)C(=O)C2=C1 MWKKTHKUEVFYQR-UHFFFAOYSA-N 0.000 description 1
YSBUMMCUZXUSQM-UHFFFAOYSA-N methyl 2-(cyanomethyl)-6-fluoro-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound C1=C(F)C=C2C(C(=O)OC)C(=O)N(CC#N)C(=O)C2=C1 YSBUMMCUZXUSQM-UHFFFAOYSA-N 0.000 description 1
VRDRWIRJPFJGHV-UHFFFAOYSA-N methyl 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluoro-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound O=C1C2=CC=C(F)C=C2C(C(=O)OC)C(=O)N1CC1=CC=C(Br)C=C1F VRDRWIRJPFJGHV-UHFFFAOYSA-N 0.000 description 1
VUNCRCXKVHXKLV-UHFFFAOYSA-N methyl 3-methoxy-1-oxoisochromene-4-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=C(OC)OC(=O)C2=C1 VUNCRCXKVHXKLV-UHFFFAOYSA-N 0.000 description 1
ZQKOHJNKCBIYFQ-UHFFFAOYSA-N methyl 6-fluoro-3-methoxy-1-oxoisochromene-4-carboxylate Chemical compound C1=C(F)C=C2C(C(=O)OC)=C(OC)OC(=O)C2=C1 ZQKOHJNKCBIYFQ-UHFFFAOYSA-N 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
235000010446 mineral oil Nutrition 0.000 description 1
238000002156 mixing Methods 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
230000004660 morphological change Effects 0.000 description 1
VSPPONOIKZXUBJ-UHFFFAOYSA-N n,n-diethylethanamine;oxolane Chemical compound C1CCOC1.CCN(CC)CC VSPPONOIKZXUBJ-UHFFFAOYSA-N 0.000 description 1
229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
239000002997 ophthalmic solution Substances 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
210000000578 peripheral nerve Anatomy 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
229960003243 phenformin Drugs 0.000 description 1
239000006187 pill Substances 0.000 description 1
235000015320 potassium carbonate Nutrition 0.000 description 1
239000000047 product Substances 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
210000001525 retina Anatomy 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
239000003826 tablet Substances 0.000 description 1
238000012360 testing method Methods 0.000 description 1
238000012956 testing procedure Methods 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
229960002277 tolazamide Drugs 0.000 description 1
229960005371 tolbutamide Drugs 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Landscapes

Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Engineering & Computer Science (AREA)
Life Sciences & Earth Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Veterinary Medicine (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Public Health (AREA)
Pharmacology & Pharmacy (AREA)
Diabetes (AREA)
Ophthalmology & Optometry (AREA)
Endocrinology (AREA)
Obesity (AREA)
Hematology (AREA)
Emergency Medicine (AREA)
Urology & Nephrology (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Reproductive Health (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Other In-Based Heterocyclic Compounds (AREA)

CA002042112A 1990-05-21 1991-05-08 N'-alkylspiro-isoquinoleinepyrrolidinetetrones et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase Expired - Fee Related CA2042112C (fr)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
CA002324636A CA2324636A1 (fr)	1990-05-21	1991-05-08	1, 2, 3, 4, - tetrahydro - 1, 3 - dioxo - 4 - acide isoquinolinecarboxylic methyl esters

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US07/526,362 US5045544A (en)	1990-05-21	1990-05-21	N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
US526,362		1990-05-21

Related Child Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002324636A Division CA2324636A1 (fr)	1990-05-21	1991-05-08	1, 2, 3, 4, - tetrahydro - 1, 3 - dioxo - 4 - acide isoquinolinecarboxylic methyl esters

Publications (2)

Publication Number	Publication Date
CA2042112A1 CA2042112A1 (fr)	1991-11-22
CA2042112C true CA2042112C (fr)	2001-07-24

Family

ID=24097027

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002042112A Expired - Fee Related CA2042112C (fr)	1990-05-21	1991-05-08	N'-alkylspiro-isoquinoleinepyrrolidinetetrones et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase

Country Status (5)

Country	Link
US (1)	US5045544A (fr)
EP (1)	EP0458549A1 (fr)
JP (1)	JP3398391B2 (fr)
CA (1)	CA2042112C (fr)
SG (1)	SG47697A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5068332A (en) *	1990-10-12	1991-11-26	American Home Products Corporation	Alkylidene analogs of 1'-aminospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones useful as aldose reductase inhibitors
US5189168A (en) *	1991-11-25	1993-02-23	American Home Products Corporation	1'-amino-2[(benzothiazolyl)methyl]spiro-[isoquinoline-4(1H),3'-pyrrolidine]-1,2'3,5'(2H)-tetrones and analogs thereof useful as aldose reductase inhibitors
US5189167A (en) *	1991-11-25	1993-02-23	American Home Products Corporation	Alkylidene analogs of 1'-amino-2-[(benzothiazolyl)-methyl]spiro [isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones useful as aldose reductase inhibitors
US5189044A (en) *	1992-03-20	1993-02-23	American Home Products Corporation	Isoquinoline-1,3-dione acetyl carbamates useful as aldose reductase inhibitors
JP2001213874A (ja) *	1999-07-22	2001-08-07	Mercian Corp	イソクマリン誘導体の製造およびそのための中間体
JP2001097970A (ja) *	1999-07-27	2001-04-10	Mercian Corp	イソクマリン誘導体の製造方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
AU617541B2 (en) *	1988-10-20	1991-11-28	Wyeth	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
US4927831A (en) *	1988-10-20	1990-05-22	American Home Products	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors

1990
- 1990-05-21 US US07/526,362 patent/US5045544A/en not_active Expired - Lifetime
1991
- 1991-05-08 CA CA002042112A patent/CA2042112C/fr not_active Expired - Fee Related
- 1991-05-17 EP EP19910304483 patent/EP0458549A1/fr not_active Ceased
- 1991-05-20 JP JP11447891A patent/JP3398391B2/ja not_active Expired - Fee Related
1996
- 1996-05-17 SG SG1996003837A patent/SG47697A1/en unknown

Also Published As

Publication number	Publication date
CA2042112A1 (fr)	1991-11-22
JP3398391B2 (ja)	2003-04-21
JPH04226983A (ja)	1992-08-17
US5045544A (en)	1991-09-03
EP0458549A1 (fr)	1991-11-27
SG47697A1 (en)	1998-04-17

Legal Events

Date	Code	Title	Description
1998-03-27	EEER	Examination request
2005-05-09	MKLA	Lapsed

Publication	Publication Date	Title
CA2042113C (fr)	2001-08-28	Spiro-isoquinoleinepyrrolidine et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase
US4927831A (en)	1990-05-22	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
EP0365324B1 (fr)	1994-05-04	Spiro-isoquinoléine-pyrrolidine-tétrones et leurs analogues utiles comme inhibiteurs de l'aldoseréductase
CA2042112C (fr)	2001-07-24	N'-alkylspiro-isoquinoleinepyrrolidinetetrones et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase
CA2093793C (fr)	2001-08-21	Analogues alkylideniques de 1'-aminospiro¬isoquinoleine-4(1h),3'-pyrrolidine\|-1,2',3,5'(2h)-tetrones, utiles comme inhibiteurs de l'aldose-reductase
US5130425A (en)	1992-07-14	Spiro-lactams and analogs thereof useful as aldose reductase inhibitors
CA2093794C (fr)	2002-01-22	1'-aminospiro¬isoquinoleine-4(1h),3'-pyrrolidine\|-1,2',3,5'(2h)-tetrones, utiles comme inhibiteurs de l'aldose-reductase
US5081241A (en)	1992-01-14	Spiro-pyridazines and analogs thereof useful as aldose reductase inhibitors
US5093496A (en)	1992-03-03	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
US5189168A (en)	1993-02-23	1'-amino-2[(benzothiazolyl)methyl]spiro-[isoquinoline-4(1H),3'-pyrrolidine]-1,2'3,5'(2H)-tetrones and analogs thereof useful as aldose reductase inhibitors
CA2324636A1 (fr)	1991-11-22	1, 2, 3, 4, - tetrahydro - 1, 3 - dioxo - 4 - acide isoquinolinecarboxylic methyl esters
AU665796B2 (en)	1996-01-18	1'-amino-2-((benzothiazolyl)methyl)spiro (isoquinoline-4(1H),3'-pyrrolidine)-1,2',3,5'(2H)-tetrones and analogs thereof useful as aldose reductase inhibitors
US5189167A (en)	1993-02-23	Alkylidene analogs of 1'-amino-2-[(benzothiazolyl)-methyl]spiro [isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones useful as aldose reductase inhibitors
US4983613A (en)	1991-01-08	Isoquinoline acetic acids and acetyl carbamates useful as aldose reductase inhibitors
HK1010368A (en)	1999-06-17	N-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
HK1011356B (en)	2000-05-12	Alkylidene analogs of 1'-aminospiro[isoquinoline-4(1h), 3'-pyrrolidine]-1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors in vivo
IE913604A1 (en)	1992-04-22	1'-aminospiro[isoquinoline-4(1h),3'-pyrrolidine]-1,2',3,5'¹(2h)-tetrones and analogs thereof useful as aldose reductase¹inhibitors
HK1004067B (en)	1998-11-13	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
GB2252321A (en)	1992-08-05	Isoquinoline intermediates preparation
HK1009601B (en)	2000-05-12	1'-aminospiro[isoquinoline-4(1h),3'-pyrrolidine]-1,2',3,5'(2h)-tetrones and analogs thereof useful as aldose reductase inhibitors in vivo